Drug Interaction Report

ADJUST DOSE: Coadministration with ranolazine may increase the plasma concentrations of digoxin. The mechanism is ranolazine inhibition of the P-glycoprotein-mediated efflux of digoxin in the intestine. In healthy volunteers, coadministration of ranolazine (1000 mg twice a day) and digoxin (0.125 mg once a day) resulted in a 1.5-fold increase in the plasma concentrations of digoxin. In contrast, digoxin did not increase the plasma concentrations of ranolazine, which is also a substrate of P-glycoprotein.

MANAGEMENT: Digoxin dosage may need adjustment during coadministration with ranolazine. Pharmacologic response and serum digoxin levels should be monitored more closely whenever ranolazine is added to or withdrawn from therapy, and the digoxin dosage adjusted as necessary. Patients should be advised to notify their physician if they experience signs and symptoms of digoxin toxicity such as irregular heartbeats, slow pulse, nausea, anorexia, or visual changes.

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of orally administered ranolazine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because ranolazine prolongs QT interval in a dose-dependent manner, high plasma levels of ranolazine may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes.

MANAGEMENT: Patients treated with ranolazine should avoid consumption of grapefruit juice and other grapefruit products if possible. Otherwise, the dosage of ranolazine should be limited to 500 mg twice a day.

Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits. In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water. Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin. Thus, the interaction is unlikely to be of clinical significance.